Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Technical University of Munich (TUM), 85748 Garching, Germany.
Int J Mol Sci. 2021 Jul 12;22(14):7474. doi: 10.3390/ijms22147474.
Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare multisystem premature aging disorder that leads to early death (mean age of 14.7 years) due to myocardial infarction or stroke. Most cases have a de novo point mutation at position G608G within exon 11 of the gene. This mutation leads to the production of a permanently farnesylated truncated prelamin A protein called "progerin" that is toxic to the cells. Recently, farnesyltransferase inhibitor (FTI) lonafarnib has been approved by the FDA for the treatment of patients with HGPS. While lonafarnib treatment irrefutably ameliorates HGPS disease, it is however not a cure. FTI has been shown to cause several cellular side effects, including genomic instability as well as binucleated and donut-shaped nuclei. We report that, in addition to these cellular stresses, FTI caused an increased frequency of cytosolic DNA fragment formation. These extranuclear DNA fragments colocalized with cGAs and activated the cGAS-STING-STAT1 signaling axis, upregulating the expression of proinflammatory cytokines in FTI-treated human HGPS fibroblasts. Treatment with lonafarnib and baricitinib, a JAK-STAT inhibitor, not only prevented the activation of the cGAS STING-STAT1 pathway, but also improved the overall HGPS cellular homeostasis. These ameliorations included progerin levels, nuclear shape, proteostasis, cellular ATP, proliferation, and the reduction of cellular inflammation and senescence. Thus, we suggest that combining lonafarnib with baricitinib might provide an opportunity to reduce FTI cellular toxicity and ameliorate HGPS symptoms further than lonafarnib alone.
亨廷顿舞蹈病-吉福德早衰综合征（Hutchinson-Gilford progeria syndrome，HGPS）是一种罕见的多系统过早衰老疾病，由于心肌梗死或中风，患者通常在 14.7 岁之前死亡。大多数病例在 基因的第 11 外显子中的位置 G608G 处存在从头发生的点突变。该突变导致产生一种称为“progerin”的永久法呢基化截短的前层粘连蛋白 A 蛋白，该蛋白对细胞有毒性。最近，法尼基转移酶抑制剂（farnesyltransferase inhibitor，FTI）lonafarnib 已被 FDA 批准用于治疗 HGPS 患者。虽然 lonafarnib 治疗无疑改善了 HGPS 疾病，但它并不是一种治愈方法。FTI 已被证明会引起几种细胞副作用，包括基因组不稳定性以及双核和甜甜圈形核。我们报告说，除了这些细胞应激外，FTI 还导致细胞质 DNA 片段形成的频率增加。这些核外 DNA 片段与 cGAs 共定位并激活了 cGAS-STING-STAT1 信号通路，上调了 FTI 处理的人类 HGPS 成纤维细胞中促炎细胞因子的表达。用 lonafarnib 和 JAK-STAT 抑制剂 baricitinib 治疗不仅阻止了 cGAS-STING-STAT1 通路的激活，而且改善了整体 HGPS 细胞内稳态。这些改善包括 progerin 水平、核形状、蛋白质稳态、细胞 ATP、增殖以及减少细胞炎症和衰老。因此，我们建议将 lonafarnib 与 baricitinib 联合使用可能有机会降低 FTI 的细胞毒性，并进一步改善 HGPS 症状，优于单独使用 lonafarnib。
